The most common grade AEs associated with the soluble fusion
The most common grade 3/4 AEs associated with the soluble fusion protein ziv-aflibercept are neutropenia, hypertension, and diarrhea . In general, medical oncologists associate ziv-aflibercept with worse toxicity than BV, and meta-analyses of clinical trial data with ziv-aflibercept or BV support this association. A meta-analysis of 4310 patients in 10 clinical trials of aflibercept in various cancers demonstrated a RR for developing serious infections of 2.68 (95% CI, 2.34–3.08; P < 0.001), which is notably higher than that reported for BV (RR, 1.59; 95% CI, 1.42–1.79; P < 0.001) , . Aflibercept has also been shown to be associated with a significantly increased risk of developing β-Sitosterol (all- and high-grade)  and proteinuria (all- and high-grade)  compared with controls in meta-analyses of clinical trials of cancer patients. Furthermore, both ramucirumab and aflibercept were associated with a significant increase in high-grade cardiotoxicity versus controls in a meta-analysis of trials in patients with solid tumors (relative risk of high-grade event was 5.0 [95%CI, 0.01–77.19] for ramucirumab and 4.1 [95%CI, 0.73–72.78] for aflibercept) .
The risk of thrombosis, gastrointestinal perforation, and hemorrhage appear less with TKIs than with BV, which may be due to a compensatory mechanism (VEGF elevation) with TKIs . A meta-analysis of 27 RCTs in cancer patients receiving TKIs showed the incidence of all-grade and high-grade hemorrhagic events to be 9.1% and 1.3%, respectively . While TKIs were associated with an increased risk of hemorrhagic events versus control (placebo, chemotherapy or EGFR TKI), this was primarily for low-grade events; commonly reported events were hemoptysis and epistaxis. Risk of high-grade hemorrhagic events was not increased with TKIs . Many TKIs are multi-targeted, and these additional pathways may lead to differences in observed AE profiles. The most common AEs associated with approved antiangiogenic TKIs, summarized in Table 1, are somewhat varied but generally include diarrhea or gastrointestinal disorders, fatigue, elevated liver enzymes, and hypertension. Indeed, a network meta-analysis of 72 RCTs (30013 cancer patients) showed that VEGFR TKIs were associated with development of all-grade (relative risk, 3.85; 95% CI, 3.37–4.40; P < 0.001) and high-grade hypertension (relative risk, 4.60; 95% CI, 3.92–5.40; P < 0.001) versus control . The risk of cardiotoxicity was also significantly increased with VEGFR TKIs compared with controls (primarily placebo or chemotherapy) in a meta-analysis of patients with solid tumors . As a drug category, relative risk of high-grade cardiotoxicity with VEGFR TKIs (sunitinib and sorafenib) was 5.62 (95% CI, 1.49–21.24). The highest relative risk of high-grade events was observed with vandetanib (relative risk, 7.71; 95% CI, 1.04–56.99); however, this was not included in the category ‘VEGFR TKIs’ as it also targets EGFR . Of note, typical AEs commonly associated with antiangiogenic agents occur less frequently with nintedanib than with other compounds. For example, in the phase III LUME-Lung 1 study, the incidence of gastrointestinal perforations, hypertension, bleeding and thromboembolism with nintedanib plus docetaxel was low, and similar to that observed with docetaxel alone . Several TKIs, including regorafenib, sorafenib, sunitinib, axitinib, and cabozantinib, are also associated with rash or dermatological events (Table 1).
Introduction Clausena anisum-olens (Blanco) Merr. is a synonym of Clausena sanki (Perr.) Molino which belongs to the Rutaceae family. It is a shrub growing wild and cultivated from Philippines and South China in Southeast Asia . It is not only used as a condiment, but also a multipurpose traditional medicinal herb for treating dysentery and arthritis for hundreds of years . Meanwhile, it also has the functions of dredging intestines and stomach, relieving dyspepsia, and promoting digestion , . Different plant parts have biological activities which are antibacterial , tumor-promotion inhibitory , and antioxidant  activities. Previous phytochemical studies have indicated that C. sanki contained coumarins , cyclopeptides , and essential oils , , .